The importance of threshold dose‐distribution data for priority allergens and the need for future studies
Authors: François Graham, Alessandro Fiocchi
Journal: Allergy (2022)

Food allergy is a growing global public health concern. A frequent source of anxiety for patients living with food allergies is the fear of reacting to small amounts of allergens, including labeled foods with precautionary allergen warnings such as "May contain".1 Current use of precautionary allergen labeling (PAL) is voluntary and not regulated. Ongoing discussions of scientists and food manufacturers to better regulate PAL involve using population thresholds to help the food industry determine when to apply PAL for certain priority allergens.2 Sesame ranks fourth sensitizer food among European populations3 and is included in the list of 14 major food allergens in Europe since 2006.4 It is also considered as a global priority allergen in a recent report by the World Health Organization & Food and Agriculture Organization of the United Nations, based on prevalence, severity, and potency of allergens for IgE-mediated food allergies.5 In the United States, the Food Allergy Safety, Treatment, Education, and Research Act of 2021 added sesame to the definition of a "major food allergen," effective after January 1st, 2023.6 This underlines the importance of having credible population thresholds for sesame allergy, as we already have for many other major food allergens. Population thresholds or eliciting doses (EDs) are obtained by dose distribution models from food challenges (FCs) performed in clinical practice or in research protocols. Factors that can affect robustness of threshold models include FC related-factors (double-blind placebo-controlled vs open food challenge, starting dose, number of doses given, type of allergen used, FC interpretation, subjective vs objective symptoms…), and differences in patient sub-populations (children vs adults, race/ethnicity, geographical differences). Other real-life factors that can affect the severity of a reaction in the community but are not usually present during a controlled FC also need to be taken into account (uncontrolled asthma and other intrinsic comorbidities, cofactors such as exercise and viral infections, quantity of allergen ingested in one dose rather than incremental doses as in OFC…). Finally, an important aspect of patient selection which can affect data generalizability is that in clinical practice patients with recent anaphylaxis and more severe food-allergy phenotypes are generally not considered for FC.7 For this reason, the calculated thresholds could be overestimated, especially when data are derived from retrospective studies with patients seen in clinical practice. Despite these limitations, population thresholds are the only current possibility to establish a level of danger that can be useful for precautionary allergen labeling. Moreover, a higher number of data points derived from FCs can help improve the accuracy of population threshold estimations and lower potential biases. The Voluntary Incidental Trace Allergen Labelling (VITAL) Scientific Expert Panel provided updated population EDs for 14 priority allergens in 2019 (Vital 3.0).8 In this report, sesame contained only 40 individual data points,8 five of whom unpublished. In this context, the study by Turner and colleagues9 is timely, as 246 positive sesame FCs were identified from 11 studies (including data from open FCs), with five studies added since 2019 representing 120 sesame-allergic patients. Further studies are needed to address other global priority and emerging allergens with limited or no data (i.e., many tree nuts, lupin, mustard, buckwheat, celery, crustacea other than shrimp, mollusks)5 to help provide data to improve the accuracy of threshold dose-distributions for these foods. These data are of utmost importance as they can provide reference doses that could help determine when to apply PAL. The use of PAL based on scientific population threshold data could better guide the food industry toward allergen risk-assessment and risk-management, which could ultimately improve the meaning of PAL for consumers with food allergy. Not applicable. Dr François Graham has no conflict of interest to declare. Dr Alessandro Fiocchi has consultancy fees and sponsored research with Ferrero SpA.